Cellular Engineering and Isotope Diagnostics Lab, Department of Physiology, Jagiellonian University Medical College, 31-531, Krakow, Poland.
Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland.
Inflammopharmacology. 2024 Jun;32(3):2049-2060. doi: 10.1007/s10787-024-01458-3. Epub 2024 Apr 3.
Gastric ulcers affect approx. 10% of population. Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid (ASA) predispose to or impair the physiologically complex healing of pre-existing ulcers. Since HS is an endogenous cytoprotective molecule, we hypothesized that new HS-releasing ASA-derivative (ATB-340) could overcome pathological impact of NSAIDs on GI regeneration.Clinically translational gastric ulcers were induced in Wistar rats using state-of-the-art microsurgical model employing serosal application of acetic acid. This was followed by 9 days long i.g. daily treatment with vehicle, ATB-340 (6-24 mg/kg) or equimolar ASA doses (4-14 mg/kg). Ulcer area was assessed macro- and microscopically. Prostaglandin (PG)E2 levels, indicating pharmacological activity of NSAIDs and 8-hydroxyguanozine content, reflecting nucleic acids oxidation in serum/gastric mucosa, were determined by ELISA. Qualitative and/or quantitative pathway-specific alterations at the ulcer margin were evaluated using real-time PCR and mass spectrometry-based proteomics.ASA, unlike ATB-340, dose-dependently delayed/impaired gastric tissue recovery, deregulating 310 proteins at the ulcer margin, including Ras signalling, wound healing or apoptosis regulators. ATB-340 maintained NSAIDs-specific cyclooxygenase-inhibiting capacity on systemic and GI level but in time-dependent manner. High dose of ATB-340 (24 mg/kg daily), but not ASA, decreased nucleic acids oxidation and upregulated anti-oxidative/anti-inflammatory heme oxygenase-1, 24-dehydrocholesterol reductase or suppressor of cytokine signalling (SOCS3) at the ulcer margin.Thus, ASA impairs the physiological healing of pre-existing gastric ulcers, inducing the extensive molecularly functional and proteomic alterations at the wound margin. HS-releasing ATB-340 maintains the target activity of NSAIDs with limited impact on gastric PGE2 signalling and physiological GI regeneration, enhancing anti-inflammatory and anti-oxidative response, and providing the pharmacological advantage.
胃溃疡影响约 10%的人口。非甾体抗炎药（NSAIDs），包括乙酰水杨酸（ASA），容易导致或损害原有溃疡的生理复杂愈合。由于 HS 是一种内源性细胞保护分子，我们假设新的 HS 释放 ASA 衍生物（ATB-340）可以克服 NSAIDs 对 GI 再生的病理影响。我们使用最新的显微外科模型在 Wistar 大鼠中诱导临床转化性胃溃疡，该模型采用醋酸的浆膜应用。随后进行 9 天的口服每日治疗，给予载体、ATB-340（6-24mg/kg）或等摩尔 ASA 剂量（4-14mg/kg）。通过宏观和微观评估溃疡面积。通过 ELISA 测定前列腺素（PG）E2 水平，指示 NSAIDs 的药理活性，以及血清/胃黏膜中 8-羟基鸟嘌呤含量，反映核酸氧化。使用实时 PCR 和基于质谱的蛋白质组学评估溃疡边缘的定性和/或定量途径特异性改变。ASA 与 ATB-340 不同，剂量依赖性地延迟/损害胃组织恢复，使溃疡边缘的 310 种蛋白质失调，包括 Ras 信号、伤口愈合或细胞凋亡调节剂。ATB-340 在全身和 GI 水平上保持 NSAIDs 特异性环氧化酶抑制能力，但具有时间依赖性。高剂量的 ATB-340（每天 24mg/kg），而不是 ASA，可降低核酸氧化并上调抗氧化/抗炎血红素加氧酶-1、24-脱氢胆固醇还原酶或细胞因子信号转导抑制物（SOCS3）在溃疡边缘。因此，ASA 会损害原有胃溃疡的生理愈合，在伤口边缘引起广泛的分子功能和蛋白质组改变。释放 HS 的 ATB-340 维持 NSAIDs 的靶活性，对胃 PGE2 信号和生理 GI 再生的影响有限，增强抗炎和抗氧化反应，并提供药理优势。
